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Rheumatol Int (2010) 30:10051015

DOI 10.1007/s00296-009-1086-1
1 3
ORI GI NAL ARTI CLE
Patient-reported-outcomes in subjects with painful lumbar
or cervical radiculopathy treated with pregabalin: evidence
from medical practice in primary care settings
Mara Teresa Saldaa Ana Navarro
Concepcin Prez Xavier Masramn Javier Rejas
Received: 28 October 2008 / Accepted: 5 August 2009 / Published online: 2 October 2009
The Author(s) 2009. This article is published with open access at Springerlink.com
Abstract The objective of this study was to evaluate the
eVect of pregabalin in painful cervical or lumbosacral
radiculopathy treated in Primary Care settings under rou-
tine clinical practice. An observational, prospective 12-
week secondary analysis was carried-out. Male and female
above 18 years, nave to PGB, with refractory chronic pain
secondary to cervical/lumbosacral radiculopathy were
enrolled. SF-MPQ, Sheehan Disability Inventory, MOS
Sleep Scale, Hospital Anxiety and Depression Scale and the
EQ-5D were administered. A total of 490 (34%) patients
were prescribed PGB-monotherapy, 702 (48%) received
PGB add-on, and 159 (11%) were administered non-PGB
drugs. After 12 weeks, signiWcant improvements in pain,
associated symptoms of anxiety, depression and sleep dis-
turbances, general health; and level of disability were
observed in the three groups, being signiWcantly greater in
PGB groups. In routine medical practice, monotherapy or
add-on pregabalin is associated with substantial pain allevi-
ation and associated symptoms improvements in painful
cervical or lumbosacral radiculopathy.
Keywords Radiculopathy Pregabalin Primary health
care Epidemiologic studies Outcomes research Clinical
practice
Introduction
Spinal pain is the most common form of chronic pain [1],
with prevalences of back pain in the general population of
1545% [24], and of 1322% in the case of cervical pain
[57]. A neuropathic mechanism is implied in the genesis
of this type of pain in 1019% of all patients with back pain
[810], resulting in impaired quality of life, and increased
utilization of health care resources and economical cost
[1012]. As in other types of chronic pain, patients with
back pain not only suVer important comorbidities in the
form of other painful disorders [1012], but frequently also
present with prominent sleep disturbances [13], as well as
anxiety and mood disorders [14, 15].
Despite the introduction of new treatments, the manage-
ment of patients with neuropathic pain remains a challenge
[16]. In clinical practice, patients with neuropathic pain
including those with spinal pain, often receive suboptimal
treatment. In this context, the most widely used pharmaco-
logical treatments in these patients are nonsteroidal antiin-
Xammatory drugs [1012], which are scantly eVective in
the management of pain with a neuropathic component
such as the one found in radiculopathies [17]. Such subopti-
mal treatment of neuropathic pain contributes substantially
M. T. Saldaa (&)
Centro de Salud de Races, Av. del Campn 67,
33400 Castrilln (Asturias), Spain
e-mail: zatosaldana@yahoo.es
M. T. Saldaa
Races Primary Care Center, Castrilln, Asturias, Spain
A. Navarro
Puerta del ngel Primary Care Center, Madrid, Spain
C. Prez
Pain Clinic, De la Princesa Hospital, Madrid, Spain
X. Masramn
Department of Statistics,
European Biometrics Institute, Barcelona, Spain
J. Rejas
Health Outcomes Research Department,
Medical Unit, PWzer Spain, Alcobendas, Spain
e-mail: olga.freire@pWzer.com
1006 Rheumatol Int (2010) 30:10051015
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to the patient disease burden [1820]. Although a number
of therapies are available for neuropathic pain, including
antidepressants, tramadol, opioids, and diVerent antiepilep-
tic drugs, the results of a recent systematic review suggest
that, in view of their balance between eYcacy and tolerabil-
ity, gabapentin and pregabalin (PGB) can be regarded as
Wrst line treatments for peripheral pain with a neuropathic
component [16]. In addition, these antiepileptic drugs,
together with antidepressants, oVer the advantage of acting
not only on pain but also on the associated symptoms of
depression [16]. The presence of psychological disorders in
these subjects may exacerbate pain intensity and disability.
Therefore, treatment with anticonvulsive drugs or antide-
pressants could optimize treatment eVectiveness and reduce
the occurrence of adverse events [21].
Pregabalin (PGB) is a structural analog of gamma-
aminobutyric acid (GABA) that selectively binds the
alpha
2
-delta (
2
-) subunit, of voltage-dependent calcium
channels, and which possesses analgesic, anxiolytic, and
antiepileptic properties [22]. In placebo controlled clinical
trials, PGB has demonstrated eYcacy in ameliorating pain
relief and in improving the aVective component of pain and
sleep disturbances in patients with peripheral diabetic neu-
ropathy [2326], postherpetic neuralgia [2729], and spinal
cord injury, a model of central neuropathic pain [30].
However, there is no information on the eVect of PGB in
patients with cervical or lumbosacral radiculopathy under
routine clinical practice (real world conditions), these
patients representing up to two-thirds of all cases of neuro-
pathic pain in same studies [10].
The present work was conducted to show evidence from
the clinical practice of the eVect of PGB upon diVerent
Patient-Reported-Outcomes (PROs), representative of the
multidimensional nature of these disorders, in a large group
of subjects with painful cervical or lumbosacral radiculopa-
thy treated in the primary care setting under conditions of
routine clinical practice.
Methods
Study design
This work presents the results of a secondary analysis of a
multicentre, observational (naturalistic) and prospective 12-
week study, whose objective was to assess the cost of
refractory painful radiculopathy of cervical or lumbosacral
origin in Primary Care Settings under real life conditions:
the LIRA study [31]. The study was carried out between
September 2005 and April 2006, and involved the partici-
pation of 381 primary care physicians randomly selected by
quotas according to regional population density in Spain.
This was a non-interventional study, and the analgesic
treatment administered to the patients was determined by
the clinical judgment of the supervising physician. The
physician could substitute previous treatment with some
other drug, or add a new drug to the existing treatment. In
accordance to the Spanish recommendations, the study was
approved by the Ethics Committee of Hospital de la Princ-
esa (Madrid), and it was conducted in agreement with the
principles contained in the Declaration of Helsinki for stud-
ies in humans.
The objective of this secondary analysis was to compare
the eVect of two patterns of PGB treatment, add-on and
monotherapy (PGB add-on and PGB monotherapy groups),
when compared with a treatment pattern not including PGB
(non-PGB group) on pain alleviation and associated symp-
toms involving depression, anxiety, sleep, disability and,
quality of life.
Study population
The original study included patients of both genders aged
18 years or older. The subjects were refractory to previous
analgesia and suVered chronic pain with a duration of over
6 months. Refractory was deWned as no pain reduction after
treatment with at least one course of an analgesic in mono-
therapy. The pain was secondary to cervical radiculopathy,
deWned as neck pain irradiating towards the arms, or to
lumbosacral radiculopathy, deWned as lumbar or sacral pain
irradiating to the calves or feet and exhibiting a distribution
consistent with involvement of nerve root L5 or S1, respec-
tively. In addition, the patients were required to present a
score of 4 in the DN4 neuropathic pain diagnostic ques-
tionnaire (see below), have a suYcient cultural and educa-
tional level to complete health questionnaires written in
Spanish, and give their informed consent. This secondary
analysis only included those patients who met the afore-
mentioned selection criteria, and who had not received
treatment with PGB prior to the start of the study.
The study sample size was deWned for the primary end-
point of the LIRA study, i.e., the determination of cost and
its evolution after 12 weeks of follow-up, under conditions
of routine clinical practice in the PCS. Therefore, no sam-
ple size predetermination was made for the secondary anal-
ysis presented in this work.
Clinical evaluations and measurement instruments
The patients were followed-up for 12 weeks, and were
evaluated twice: at baseline and at end of study. At the
baseline visit, the clinicians administered the DN4 neuro-
pathic pain diagnostic questionnaire, the selection criteria
were checked, and patient sociodemographic data were
collected, along with information on the duration of the
disease and its treatment, and the use of health care and
Rheumatol Int (2010) 30:10051015 1007
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non-health care resource utilization in the 12 weeks prior to
patient inclusion, as reXected in the patient case history. On
both the baseline visit and after the 12 weeks of follow-up,
the patients were required to complete the Short-Form
McGill Pain Questionnaire (SF-MPQ), the Sheehan Dis-
ability Inventory (SDI), the Medical Outcomes Study Sleep
Scale (MOS), the Hospital Anxiety and Depression Scale
(HADS), and the EQ-5D. In addition, the patients kept a
diary, with weekly recordings of pain intensity [visual ana-
log scale (VAS) of the SF-MPQ] and health status (health
status VAS of the EQ-5D).
The DN4 (Douleur Neuropathique 4 questions) neuro-
pathic pain diagnostic questionnaire consists of 10 items
that describe diVerent pain characteristics, and allows dis-
crimination of neuropathic pain from non-neuropathic pain.
If the patient exhibits a score of at least 4 out of 10 possible
points (range 010), the patient is considered to have neu-
ropathic pain, with a sensitivity of 83% and a speciWcity of
90% [3234].
The main component of the Short-Form McGill Pain
Questionnaire (SF-MPQ) comprises 15 descriptors (11 sen-
sory and 4 aVective descriptors) that are scored on a scale
of 0 = no pain to 3 = severe pain [35]. The sum of the
diVerent intensities in turn yields three pain scores: sensory,
aVective, and total. The second part of the SF-MPQ con-
sists of a 100-mm VAS for scoring the intensity of the pain
experienced by the patient in the previous week. The third
part of the instrument is a measure of the intensity of pain at
the time of the evaluation, and involves a 6-point scale
from 0 = no pain to 5 = unbearable pain.
The Sheehan Disability Inventory (SDI) is a simple and
frequently used instrument that evaluates patient functional
alteration in three domains: work, social life/leisure, and
family life/home responsibilities [36]. Each domain is
scored on an 11-point scale from 0 = no impairment to
10 = extremely impaired. The instrument contains two
additional items that explore perceived stress and social
support. The former is likewise scored on an 11-point scale,
while perceived social support is scored on an 11-point
scale expressed as percentages from 0% = no support to
100% = ideal support. The SDI yields three scores: the dis-
ability score consisting of the sum of the scores of the Wrst
three items, ranging from 0 to 30; the fourth item (per-
ceived stress) score, ranging from 0 to 10; and the Wfth item
(social support) score, which, unlike the previous four
scores, must be inverted.
The Medical Outcomes Study Sleep Scale (MOS) is a
self-administered questionnaire that explores key aspects of
sleep [37]. It consists of 12 items distributed into 6 sub-
scales or domains: sleep disturbance, snoring, waking up
with shortness of breath or headache, the adequacy of sleep,
daytime somnolence, and amount of sleep. In addition, the
MOS-sleep provides a summarizing index of sleep
problems based on the scores of 9 of its itemsthe higher
the score is, the worse the sleep, except when referring to
the dimensions amount of sleep and adequacy of sleep,
which are interpreted in the opposite manner. The scale has
shown good psychometric properties in patients with
neuropathic pain [38].
The Hospital Anxiety and Depression Scale (HADS) is
also a self-administered instrument composed of 14 items,
of which 7 explore symptoms of depression and 7 assess
anxiety [39]. Each item is scored from 0 to 3, where 0 = no
symptom and 3 = most severe or frequent symptom. The
two scores are obtained by adding the 7 items of each sub-
scaleone relating to depression and the other to anxiety
(HADS-D and HADS-A)each score ranging from 0 to 21
points.
The EQ-5D questionnaire evaluates patient-perceived
health [40]. It oVers a generic measure of health based on 5
items that explore the degree of alteration in 5 dimensions:
mobility, personal care, daily life activities, pain/discom-
fort, and anxiety/depression. The scores of the 5 items can
be used to calculate a utility index that varies from 0.6 to
1.0, where the highest scores correspond to better patient
health. The instrument also includes a 20-cm visual analog
scale (EQ-5D VAS) ranging from 0 = worst imaginable
health status to 100 = best imaginable health status.
As the original study was designed as an observational
epidemiological research, forced adverse events reporting
(i.e.: type of adverse event, seriousness, etc.) could not be
implemented except to document the reason for discontinu-
ation before the end of study visit.
Statistical analysis
For the statistical analysis of this secondary evaluation, and
according to the treatment prescribed from the baseline
visit as established by clinical judgment, the patients were
divided into three groups: patients that substituted or added
another drug other than PGB to previous treatment (Non-
PGB group); patients that substituted previous treatment
with PGB as monotherapy (PGB monotherapy group); and
patients that received PGB added onto the existing thera-
peutic regimen (PGB add-on group).
The baseline characteristics of the patients are reported
as the mean and standard deviation for quantitative vari-
ables, while qualitative variables are represented as
absolute and relative frequencies. Normality distribution
assumptions were veriWed using the KolmogorovSmirnov
test. Analysis of variance (ANOVA), the KruskalWallis
test, and the chi-square test were used to assess the baseline
homogeneity of the variables in the three study groups.
The proportion of patients with a reduction of at least
50% in pain intensity as rated by the SF-MPQ pain VAS
was calculated and deWned as responders. The cumulative
1008 Rheumatol Int (2010) 30:10051015
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number of days without pain or with mild pain was calcu-
lated (<40 mm on the VAS of the SF-MPQ). In addition,
the changes in the above mentioned scales and subscales
versus baseline were used as assessment variables. The
comparison between groups of the changes in quantitative
variables versus baseline was carried out by analysis of
covariance (ANCOVA), adjusting for the baseline score on
each corresponding scale and the number of previous drugs.
In turn, the changes in ordinal qualitative variables versus
baseline were evaluated by means of a logistic regression
model, adjusting for the baseline score and the number of
previous drugs. These analyses were made in application to
the included patients that completed the 12 weeks of fol-
low-up, and for whom changes in the baseline variables
could be calculated. The statistical signiWcance of the com-
parisons between treatments groups was adjusted by means
of the Tukey multiple comparisons method. All statistical
tests were two-sided, and statistical signiWcance was con-
sidered for P < 0.05.
With the purpose of evaluating the clinical signiWcance
of the changes in the diVerent measurements, a calculation
was made of the eVect size obtained, based on the diVer-
ence between the means of a given measurement before and
after treatment, divided by the corresponding standard devi-
ation measured before treatment [41]. Interpretation of the
eVect size was based on the established criterion which
considers an eVect size of 0.20 to <0.50 as small; a size of
0.50 and <0.80 as moderate; and a size of 0.80 as large
[41].
Based on the weekly patient scores corresponding to the
VAS of the EQ-5D, calculations were made of the gains in
QALYs (quality-adjusted life years) after 12 weeks of fol-
low-up. The direct VAS score divided by 100 was used as
an estimator of utility value (in metric terms 01, where
0 = death and 1 = perfect health), from which the gain in
QALYs was calculated. Trapezoidal approximation was
used for this calculation, employing the baseline and
weekly utility values as reference values [42].
Results
Patient distribution
A total of 1,879 patients were included in the LIRA study,
of which 1,351 had not been previously exposed to PGB
and met the inclusion/exclusion criteria for this secondary
analysis. The analysis was Wnally performed in 1,304
patients (96.5%) that completed the 12 weeks of the study.
Figure 1 reports these data, along with the causes of patient
losses to follow-up. Radiculopathy was of lumbar origin in
86.9% of cases, and of cervical origin in 13.1% (without
Fig. 1 Patient disposition
Rheumatol Int (2010) 30:10051015 1009
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signiWcant diVerences in this distribution according to
treatment group).
Baseline demographic and clinical characteristics
The recruited population was of middle age, with a female
predominance, and over half of the subjects were without
working activity (Table 1). On average, patients had painful
radiculopathy for 2 years and were treated with at least one
curse of an analgesic. The most frequent previous treat-
ments were analgesics, particularly nonsteroidal antiinXam-
matory drugs (NSAIDs), and paracetamol, which were used
by at least 60% and almost 50% of the subjects, respec-
tively. Frequency of previous drug use was numerically
diVerent between groups. However, except for vitamin use
(more frequently used by PGB add-on group, P < 0.001),
diVerences in the others type of drug were hardly statisti-
cally signiWcant (Table 1). The three treatment groups were
similar in terms of demographics characteristics, with the
exception of fewer previous treatments in the PGB mono-
therapy group versus the other two groups (Table 1). The
patients in the PGB add-on group generally presented with
poorer clinical conditions, with increased pain intensity,
worst social and working activity, and poorer quality of life
(Table 2). Although of questionable clinical relevance, anx-
iety levels were signiWcantly greater in the PGB add-on
group than in the other two groups (Table 2). There were no
diVerences with regard to sleep disturbances.
Drug therapy during study
Most of the patients in the non-PGB group (67%) received
two or more drugs for pain treatment [mean (SD): 2.2 (1.4)],
the most frequent being paracetamol (37%, mean dose
standard deviation: 2.144 1.010 mg/day), metamizol
(21%, 1,087 455), tramadol (19%, 157 60 mg/day), ibu-
profen (17%, 1.094 451 mg/day), diclofenac (16%, 88
49), gabapentin (13%, 989 594 mg/day), tetrazepam (8%,
65 24 mg/day), diazepam (6%, 6 3 mg/day), fentanil
(6%, 59 23 mg/day), codeine (6%, 59 23 mg/day), and
amitriptyline (5%, 38 28 mg/day). In the PGB mono-
therapy group, the mean dose was 187 106 mg/day. The
most frequently used drugs in the PGB add-on group (mean
dose: 191 107 mg/day) were paracetamol (42%, 2.146
1.077 mg/day), ibuprofen (21%, 1.218 555 mg/day), tram-
adol (20%, 163 81 mg/day), diclofenac (13%, 126 52),
metamizol (11%, 1.517 863 mg/day), tetrazepam (7%,
80 42 mg/day), diazepam (6%, mean dose 7 4 mg/day),
Table 1 Demographic
and clinical characteristics
Characteristics Non-PGB
(N = 155)
a
PGB
monotherapy
(N = 473)
a
PGB
add-on
(N = 676)
a
P
Sex (female), n (%) 90 (57.8) 262 (55.3) 377 (55.8) 0.879
Age (years), mean (SD) 56.3 (13.2) 56.0 (12.7) 57.2 (12.1) 0.230
Body mass index (kg/m
2
) 27.9 (4.2) 27.3 (3.8) 27.5 (3.8) 0.204
Marital status (married or with couple), n (%) 120 (77.2%) 342 (72.3%) 498 (73.6%) 0.525
Labor status, n (%) 0.149
Active 43 (27.9) 111 (23.3) 178 (26.3)
Housewife 26 (16.9) 70 (14.7) 114 (16.8)
Sick leave 21 (13.6) 44 (9.1) 98 (14.5)
Unemployed 9 (5.8) 18 (3.7) 26 (3.7)
Retired 46 (29.9) 199 (42.1) 231 (34.1)
Unknown 9 (5.8) 33 (7.0) 30 (4.5)
Duration (years), mean (SD) 2.1 (3.7) 2.1 (4.1) 1.9 (3.4) 0.117
No. previous treatments, mean (SD) 2.8 (1.7) 2.2 (1.3) 2.7 (1.4) <0.001
Previous treatments
b
, n (%)
NSAID 104 (67.1) 294 (62.2) 460 (68.1) 0.039
Paracetamol 75 (48.4) 207 (43.7) 317 (46.9) 0.442
Metamizol 41 (26.4) 96 (20.2) 134 (19.8) 0.174
Opioids 63 (40.6) 136 (28.8) 219 (32.4) 0.022
Antiepileptic drug 16 (10.1) 48 (10.2) 49 (7.3) 0.173
Tricyclic antidepressants 14 (8.8) 24 (5.1) 59 (8.8) 0.049
Benzodiazepines 21 (13.5) 78 (16.5) 137 (20.2) 0.077
Vitamins (B6,B12) 17 (11.0) 25 (5.3) 88 (13.1) <0.001
Others
c
10 (6.4) 19 (4.0) 78 (11.5) <0.001
NSAID Nonsteroidal antiinXam-
matory drug, SD standard
deviation, AED antiepileptic
drug, NPP neuropathic pain,
PGB pregabalin;
a
Total number of patients
analyzed; some subjects failed
to report the data relating
to certain variables
b
The patients could have
received more than one
previous treatment
c
Includes lidocaine, corticoids
1010 Rheumatol Int (2010) 30:10051015
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amitriptyline (5%, 28 20 mg/day), and fentanil (3%, mean
dose 48 23 mg/day). The mean number of drugs during
the study in this group was 2.8 (1.1).
Patient-Reported-Outcomes (PROs)
Pain reduction
The three groups showed signiWcant and clinically relevant
reductions in pain severity after 12 weeks of follow-up
(Table 3). Pain reduction proved signiWcantly greater in the
groups administered PGB, with changes of 56 and 51%,
respectively, for PGB as monotherapy and add-on treatment,
versus 36% in the patients who did not receive PGB
(P < 0.0001, Table 3). The diVerences in pain reduction were
signiWcant from the fourth week, and maintained until the
end of the study (Fig. 2)resulting in an increased cumula-
tive number of days with no/mild pain (<40 mm on the VAS
of the SF-MPQ) in the groups administered PGB versus the
patients without PGB (P < 0.0001, Table 3). At the end of
the study, 63 and 56% of the patients administered PGB as
monotherapy and on an add-on basis, respectively, showed a
50% reduction in pain intensity (responders), versus 33% in
the non-PGB group (P < 0.0001, Table 3).
Other Patient-Reported-Outcomes measurements
Improvements in comorbid conditions including sleep dis-
turbances, depression, and anxiety were signiWcantly supe-
rior in the patients administered PGB, with clinically
relevant improvement (large eVect size) while the changes
in the non-PGB group were only moderate (Tables 4 and
5). The eVect upon sleep showed a similar pattern for the
six dimensions of the MOS-sleep scale, though none of the
treatment groups showed relevant changes in the dimen-
sions snoring or waking up with shortness of breath or
headache (Table 5). On the other hand, with the exception
of sleep disturbance, which exhibited a moderate eVect
Table 2 Baseline visit patient-
reported health outcomes
Health outcome Non-PGB
(N = 155)
a
PGB
monotherapy
(N = 473)
a
PGB
add-on
(N = 676)
a
P
SF-MPQ, mean (SD)
Sensory 15.5 (5.8) 15.1 (6.0) 16.0 (6.0) 0.045
AVective 4.8 (3.3) 4.4 (3.2) 5.0 (3.2) 0.012
Total 20.3 (8.4) 19.5 (8.4) 21.0 (8.5) 0.016
PPI (05) 2.7 (0.8) 2.7 (0.8) 2.8 (0.8) 0.014
VAS (0100) 71.4 (15.3) 70.4 (14.6) 72.7 (15.3) 0.032
MOS-sleep, mean (SD)
Summary index (0100) 47.6 (16.9) 46.2 (17.2) 48.4 (17.2) 0.096
Sleep disturbance (0100) 50.6 (20.1) 48.5 (19.5) 51.96 (19.6) 0.015
Snoring (0100) 39.3 (30.6) 37.3 (28.6) 37.4 (28.6) 0.754
Shortness of breath (0100) 30.1 (25.4) 29.5 (26.6) 31.3 (26.0) 0.539
Sleep quantity, hours 5.8 (1.5) 5.8 (1.4) 5.6 (1.3) 0.004
Adequacy of sleep (1000) 39.1 (23.6) 40.0 (23.1) 36.8 (23.2) 0.067
Daytime somnolence (0100) 40.2 (19.4) 38.1 (19.0) 37.5 (19.0) 0.230
HADS, mean (SD)
Depression (021) 10.8 (4.5) 10.0 (4.5) 10.7 (4.4) 0.014
Anxiety (021) 10.5 (3.9) 9.9 (3.9) 10.6 (3.8) 0.022
SDI, mean (SD)
Disability (030)
b
18.9 (6.0) 18.4 (5.8) 20.0 (5.4) <0.001
Perceived stress (0100) 6.0 (2.1) 5.9 (2.1) 6.3 (1.9) 0.007
Perceived social support, % (0100) 58.1 (22.3) 56.0 (22.4) 57.4 (23.6) 0.503
EQ-5D
VAS, mean (SD) (0100) 42.3 (17.2) 42.5 (18.2) 38.9 (17.5) 0.002
Mobility
c
, n (%) 53 (34.9) 134 (28.9) 181 (27.0) 0.051
Personal care
c
, n (%) 59 (38.8) 203 (43.8) 264 (39.5) 0.156
Daily life activities
c
, n (%) 21 (13.8) 51 (11.1) 47 (7.0) <0.001
Without pain, n (%) 5 (3.3) 11 (2.4) 8 (1.2) 0.002
Without anxiety/depression, n (%) 37 (24.5) 127 (27.4) 150 (22.5) 0.010
SD Standard deviation, VAS
visual analog scale, HADS
Hospital Anxiety Depression
Scale, MOS Medical Outcomes
Study, PGB pregabalin,
PPI present pain intensity,
SDI Sheehan Disability
Inventory, SF-MPQ Short Form
McGill Pain Questionnaire
a
Total number of patients
analyzed; some subjects failed to
report the data relating to certain
variables
b
Sum of the scores of the three
disability items
c
Patients responding without
problems in the item
Rheumatol Int (2010) 30:10051015 1011
1 3
size, the changes in the non-PGB group for all the MOS-
Sleep dimensions were small. In contrast, the PGB-treated
groups showed large changes for sleep disturbance and
adequacy of sleep, with moderate changes for amount of
sleep and daytime somnolence (Table 5).
All treatment groups showed relevant improvement in
the impact of painful radiculopathy on patient perceived
stress and social and working activities as measured by the
SDI (Table 4). Once again, these changes were signiWcantly
greater in the two groups that received PGB. General
patient health according to the EQ-5D VAS also improved
signiWcantly more in the PGB-treated groups, and the clini-
cal impact was likewise greater as measured by the eVect
size (Table 4), in turn giving rise to a greater gain in
QALYs in the groups exposed to PGB (Table 4). These
diVerences were seen to be signiWcant from week 5 of the
study, and maintained until week 12 (Fig. 3). In general
terms, the beneWt observed in each of the Wve dimensions of
the EQ-5D was signiWcantly greater in the groups treated
with PGB, particularly among those patients that received
the drug as monotherapy (Table 4).
Discussion
Few randomized clinical trials have been run in patients
presenting with pain with a neuropathic component second-
ary to radiculopathy, and particularly in general in chronic
Table 3 Mean and magnitude of change (eVect size) of the diVerent pain parameters measured by the SF-MPQ according to treatment group
Values given as mean (standard deviation) [eVect size]
VAS Visual analog scale, PGB pregabalin, PPI present pain intensity, SF-MPQ Short Form McGill Pain Questionnaire
a
Total number of patients analyzed; some subjects failed to report the data relating to certain variables
b
Responders: patients with a reduction of at least 50% in pain intensity as scored by the VAS of the SF-MPQ
Health outcome Non-PGB (N = 155)
a
PGB monotherapy
(N = 473)
a
PGB add-on
(N = 676)
a
P
SF-MPQ
Sensory 5.1 (5.6) [0.88] 8.3 (6.3) [1.38] 8.0 (5.9) [1.33] <0.001
AVective 2.2 (2.7) [0.66] 2.9 (3.0) [0.91] 3.0 (2.9) [0.94] <0.001
Total 7.4 (7.6) [0.88] 11.2 (8.5) [1.33] 11.0 (8.0) [1.29] <0.001
PPI 0.9 (1.0) [1.13] 1.5 (1.0) [1.88] 1.4 (1.0) [1.75] <0.001
SF-MPQ intensity (VAS)
mm 25.0 (22.0) [1.63] 40.1 (23.2) [2.75] 37.1 (24.0) [2.42] <0.001
% 35.6 (27.8) 56.4 (27.6) 50.7 (27.4) <0.001
Responders (%)
b
32.9 62.8 56.3 <0.001
Cumulative days without pain
or mild pain (VAS <40 mm)
20.2 (26.9) 36.3 (29.7) 30.7 (28.9) <0.001
Fig. 2 Mean weekly change in pain intensity as scored by the VAS of
the SF-MPQ
Fig. 3 Mean weekly change in health status as scored by the VAS of
the EQ-5D
1012 Rheumatol Int (2010) 30:10051015
1 3
pain of mixed origin [16]. In addition, very few current tri-
als address the pharmacological management of these clini-
cal conditions. Our data appear to be the Wrst involving
PGB for the management of cervical and lumbosacral
radiculopathy under conditions of routine clinical practice
in the primary care setting. Our Wndings suggest that PGB
is eVective under Real World conditions for treating pain
of this kind and also for ensuring clinically relevant
improvement in the associated symptoms of anxiety,
depression, and sleep disturbanceswith amelioration of
patient disability and improvement in quality of life.
Monotherapy with PGB, or as an add-on therapy, pro-
duced a very marked decrease in pain (over 50%), with a
large eVect size. The proportion of responders, 63% and
56% in the monotherapy and add-on groups, respectively,
was at least similar to that recorded in clinical trials of PGB
among patients with diabetic neuropathy (39 and 48%)
[2325], postherpetic neuralgia (2850%) [2729], and
superior to the proportion observed in patients with central
neuropathic pain associated with spinal cord injury (22%)
[30]. The apparent analgesic superiority versus the subjects
that did not receive PGB proved consistent across all
Table 4 Mean and magnitude of change (eVect size) of the patient reported health outcomes at the end of the study, according to treatment group
Values given as mean (standard deviation) [eVect size]
VAS Visual analog scale, HADS Hospital Anxiety Depression Scale, MOS Medical Outcomes Study, PGB pregabalin, SDI Sheehan Disability
Inventory, QALY Quality-adjusted life year
a
Total number of patients analyzed; some subjects failed to report the data relating to certain variables
b
Sum of the scores of the Wrst three items
c
Patients responding without problems in the item
Health outcome Non-PGB
(N = 155)
a
PGB monotherapy
(N = 473)
a
PGB add-on
(N = 676)
a
P
HADS
Depression (021) 2.5 (4.0) [0.55] 3.9 (4.3) [0.87] 3.8 (4.2) [0.86] <0.001
Anxiety (021) 2.2 (3.4) [0.56] 3.8 (4.0) [0.97] 3.6 (3.6) [0.95] <0.001
SDI
Disability (030)
b
5.7 (5.9) [0.95] 9.2 (6.5) [1.59] 8.9 (6.3) [1.65] <0.001
Perceived stress (0100) 1.8 (2.1) [0.86] 3.0 (2.3) [1.43] 2.8 (2.2) [1.47] <0.001
Perceived social support, % (0100) 1.4 (1.8) [0.06] 2.4 (2.4) [0.11] 1.2 (1.9) [0.05] 0.004
EQ-5D
VAS (0100) 18.6 (22.3) [1.08] 29.2 (22.2) [1.60] 29.5 (21.2) [1.69] <0.001
Mobility
c
, n (%) 77 (50.7) 303 (65.3) 410 (61.1) <0.001
Personal care
c
, n (%) 90 (59.2) 360 (77.6) 487 (72.9) <0.001
Daily life activities
c
, n (%) 50 (32.9) 252 (54.7) 306 (45.7) <0.001
Without pain, n (%) 26 (17.1) 165 (35.7) 160 (23.9) <0.001
Without anxiety/depression, n (%) 74 (49.0) 302 (65.1) 388 (58.3) 0.002
QALYs gained 0.0284 (0.0409) 0.0407 (0.0389) 0.0427 (0.0369) <0.001
Table 5 Mean and magnitude of change (eVect size) of the diVerent dimensions of sleep measured by the MOS-sleep, according to treatment
group
Values given as mean (standard deviation) [eVect size]
MOS Medical Outcomes Study, PGB pregabalin
a
Total number of patients analyzed; some subjects failed to report the data relating to certain variables
Dimension of the MOS-sleep Non-PGB
(N = 155)
a
PGB monotherapy
(N = 473)
a
PGB add-on
(N = 676)
a
P
Summary index (0100) 9.3 (16.0) [0.55] 17.3 (18.1) [1.01] 17.3 (18.1) [1.01] <0.001
Sleep disturbance (0100) 11.2 (18.5) [0.56] 19.3 (20.1) [0.99] 20.0 (19.8) [1.02] <0.001
Snoring (0100) 0.9 (23.2) [0.03] 5.5 (23.6) [0.19] 5.1 (20.8) [0.18] 0.001
Shortness of breath (0100) 2.1 (27.0) [0.08] 10.7 (23.8) [0.40] 12.3 (24.7) [0.47] <0.001
Sleep quantity, hours +0.4 (1.2) [0.27] +0.9 (1.3) [0.64] +1.0 (1.2) [0.77] <0.001
Adequacy of sleep (1000) +11.3 (21.5) [0.48] +21.2 (25.3) [0.92] +20.7 (24.3) [0.89] <0.001
Daytime somnolence (0100) 5.6 (18.9) [0.29] 10.9 (19.6) [0.57] 9.5 (19.6) [0.50] <0.001
Rheumatol Int (2010) 30:10051015 1013
1 3
outcome measures, with large eVect sizes for the most part,
and likewise superior to those seen in the non-PGB
patients. These data point to the broad activity spectrum of
PGB in application to pain with a neuropathic component.
Although always diYcult to interpret in the context of an
observational study, it cannot be ruled out that this apparent
superiority may be due in part to inadequate management
of patients belonging to the non-PGB group. In a large per-
centage of cases, these latter patients were treated with
NSAIDs (67%) or paracetamol (37%). While these drugs
have an eVect upon the somatic component of pain, they
have not been shown to be eVective in the management of
neuropathic pain. In contrast, only 13% of the patients
received gabapentin, amitriptyline in 5%, and 25% received
opioids. This situation is almost analogous to that described
in other countries such as the United Kingdom or Spain,
likewise in the primary care setting, where NSAIDs are
widely used for the treatment of mixed presentations
(65%), while the use of drugs of proven clinical eYcacy in
the treatment of neuropathic pain, such as antiepileptic
agents or tricyclic antidepressants, is more limited (10 and
3%, respectively) [43, 44].
The eVect of PGB on comorbid symptoms of sleep dis-
turbances, depression, and anxiety, was signiWcantly supe-
rior in the patients administered PGB, with large eVect
sizes, versus the moderate changes seen in the non-PGB
group. Given the frequent co-occurrence of these comor-
bidities in such patients [21], the role of PGB proves partic-
ularly useful in such situations. While opiods have been
shown to be eVective in reducing neuropathic pain [16],
their beneWcial eVects upon patient mood, disability, and
quality of life are not consistent [45, 46]. In addition, the
beneWcial eVect of PGB on treating comorbid conditions
could reduce health care resource utilization and costs. As
an example, it has been reported that in patients with back
pain, existing physical and mental comorbidities, led to a
signiWcant increase in health care costs [47]. Globally, the
superior eVectiveness of PGB in ameliorating pain, and its
greater eVect upon associated comorbidities, could explain
the improvement we recorded in relation to social and
working incapacitation and quality of life, compared with
the patients administered other treatments.
The mean PGB dose used in our study, about 190 mg/
day, lies within the eVective dosing range for neuropathic
pain (150600 mg/day), and perhaps is at the lower limit
when compared with the doses used in clinical trials with
PGB. Most of the PGB trials mentioned above made use of
a Wxed-dose scheme; comparisons with our study are there-
fore diYcult to establish. However, in a randomized clini-
cal study of PGB versus placebo in patients with
neuropathic pain associated to peripheral diabetic neuropa-
thy or postherpetic neuropathy, in which a Xexible dosing
scheme was used, the mean dose was almost double what
we observed in routine practice (372 mg/day) [26].
Whether lower doses are needed in clinical practice, or
whether simple underdosing is involved, is a question
which our study was unable to answer. However, underdos-
ing seems more likely, since the prescription of doses lower
than those recommended for pain, including pain of neuro-
pathic origin, is often reported in the literature [20, 43].
Despite the lack of evidence from randomized clinical
trials, it is common in clinical practice to use combinations
of several drugs to treat pain with a neuropathic component
[4851]. In our analysis, the PGB add-on treatment group
yielded superior results compared with patients adminis-
tered other treatments, and with the exception of pain, these
results were moreover analogous to those obtained with
PGB in monotherapy. While statistically signiWcant, the
diVerences observed in pain management with PGB as
monotherapy compared with the PGB add-on group are of
scant clinical relevance for a number of reasons: the
patients in the PGB add-on group generally presented with
more severe symptoms; the diVerences in eVect size
between the two PGB-treated groups were not large; and
the impact upon patient disability and quality of life was
similar in both groups.
Our study provides data on the eVectiveness of adding
PGB to existing analgesic treatment. Nevertheless, it would
be worthwhile to conduct controlled clinical trials to evalu-
ate the possibility that PGB combined with an analgesic
could be superior to the drugs in monotherapy for the man-
agement of painful radiculopathy of mixed origin. There is
some evidence to suggest that this may be the case. Some
analgesics such as paracetamol or the NSAIDs are ineVec-
tive in application to pure neuropathic pain condition, but
may be of help in the presence of a nociceptive component.
On the other hand, a randomized and placebo controlled
trial involving the combination of pregabalin and an
NSAID has shown better performance than the drugs in
monotherapy, as preoperative analgesia in vertebral fusion
surgery [52].
Our study, however, has some limitations that must be
taken into account. Because of its observational nature, it is
exposed to bias and confounding factors. The impact of
such bias, particularly selection bias, is diYcult to establish.
However, at least in the PGB add-on treatment group, such
bias probably acts against the drug, since these were more
seriously aVected patients. On the other hand, the logical
open-label design may have overestimated the eVect of
treatment. Another limitation of our study is represented by
the fact that the study did not speciWcally assess the eVect
of pharmacological intervention, hence we have no system-
atic evaluation of the tolerability of the treatments. How-
ever, the high proportion of patients that completed the
treatment in all the groups analyzed, and the low incidence
of drop-outs attributable to adverse eVects, suggest that the
1014 Rheumatol Int (2010) 30:10051015
1 3
three treatment strategies were very well tolerated. Last, it
is worthy to comment on the diagnosis of radiculopathy in
the study. While patients were identiWed using ICD-10 clas-
siWcation criteria for radiculopathies in conjunction with a
diagnostic tool administered to assist general practitioners
in categorizing the neuropathic component of pain, we can-
not exclude the possibility of misdiagnosis to some extent.
Conclusions
Overall, in spite of these limitations, the results of this anal-
ysis complement the Wndings observed with PGB in clinical
trials, then consolidating PGB as an eVective therapy for
the treatment of the neuropathic component of pain in sub-
jects with cervical or lumbosacral radiculopathy in real
world conditions of care. This eVectiveness resulted in a
reduction of the associated symptoms of pain in routine
medical practice, leading to lower disability and better
quality of life of patients. To conclude, our analysis sug-
gests that in routine clinical practice, pregabalin both as
monotherapy and in combination, is associated with consid-
erable pain reduction, and important improvement in asso-
ciated symptoms such as sleep, aVective disorders, and
anxiety. In addition, PGB treatment reduces associated dis-
ability and improves the health condition of patients with
neuropathic pain associated with cervical or lumbosacral
radiculopathy. The possible superiority of this drug over
other treatments, the usefulness of pregabalin doses higher
than those used in this analysis, and the potential utility of
combining the drug with other treatments for the manage-
ment of this type of neuropathic pain are aspects that should be
further examined in the context of randomized clinical trials.
Acknowledgments The authors thank Fernando Rico-Villademoros
MD, for his assistance in the preparation of the draft of this manuscript.
This study was funded by an unrestricted grant from PWzer Spain.
Competing interests One of the authors of this study, Javier Rejas,
is an employee of PWzer Spain, which is the entity funding this project.
M Teresa Saldaa, Ana Navarro, and Concepcin Prez have received
honoraries from PWzer Spain.
Open Access This article is distributed under the terms of the Cre-
ative Commons Attribution Noncommercial License which permits
any noncommercial use, distribution, and reproduction in any medium,
provided the original author(s) and source are credited.
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